Cyclophosphamide (CPA) is the most widely used agent of the alkylating agent class in the clinical treatment of cancer. Two congeners, ifosfamide (IFOS, Holoxan®) and trofosfamide (Trofos, Ixoten®) are also in clinical use. CPA is still advantageous in the clinical treatment of lymphoma and breast cancer, while IFOS is effective in the clinical treatment of testicular cancer and soft tissue sarcomas and is also being used in the clinical treatment of breast cancer in the ICE (IFOS, carboplatin, etoposide) regimen. Patients with CPA-resistant breast cancer have responded to a doxorubicin-isophosphoramide mustard (IPM) based treatment, indicating the possibility of some lack of cross resistance between CPA and IPM may exist. In addition, clinical trials with IFOS for treatment of sarcoma, lymphoma and small cell lung cancers have shown an apparent lack of cross-resistance with CPA.
IFOS is converted by an activation pathway initiated by hepatic microsomes to 4-HO-IFOS, which spontaneously undergoes opening of the oxazaphosphorine ring to produce aldo-IFOS, which in turn eliminates acrolein spontaneously and/or possibly through serum albumin catalysis, generating the active metabolite, IPM. IFOS differs from CPA particularly in its metabolic dechloroethylation to produce chloroacetaldehyde. CPA generates minimal chloroacetaldehyde. Acrolein has been implicated in the dose limiting toxicity (hemorrhagic cystitis and secondary tumor promotion) noted with both IFOS and CPA.
The 4-hydroperoxide of IFOS (4-hydroperoxy IFOS; 4-HOOI) is a pre-activated form of 4-hydroxyl-IFOS, the initial hepatic metabolite of IFOS. Unfortunately 4-HOOI is too unstable to be manufactured and used for human treatment.